The basic pathogenetic mechanisms involve in inflammatory bowel disease (IBD) remain elusive. However, like other chronic inflammatory diseases, the pathogenesis appears to be multi-factorial and particularly involve complex interactions among genetic environmental and immunologic factors. The scientific fields of immunology and genetics are thought to most likely hold the answer to the puzzle of IBD and these are the major areas of investigation in this Program Project. The basic themes of this proposal thus relate to the immunologic mechanisms determining chronic inflammation in the intestine, the induction and regulation of the mucosal immune system, especially mucosal responses to enteric bacterial antigens,. The mechanisms of antigen handling in the intact and inflamed colon, and the genetic influences that determine susceptibility to disease. The strategy has been and will continue to be focused on newly developed mouse models of colitis. Although no model exactly duplicates human IBD, models can allow important insight into disease mechanisms. The mouse has been chosen because of the rich array of techniques and reagents available only in this species in both immunology and genetics. The Program Project will be directed by Dr. Charles Elson and will consist of four Projects and two Cores. Project 1, headed by Dr. Charles Elson, will focus on T cells reactive with antigens in the enteric bacterial flora, whether intestinal bacterial antigens induce tolerance or immunity, and the regulatory T cells that limit pathogenic responses in the intestinal, particularly Tr1 cells. Project 2, headed by Dr. Jerry McGhee, will explore Project 3, headed by Dr. Casey Weaver, using a noel antigen-specific model system, will address antigen interactions that maintain normal mucosal homeostasis and thus prevent chronic intestinal inflammation. Project 4, headed by Dr. Edward Leiter, is located at the Jackson Laboratory in Bar Harbor, ME. This project will map genes important in susceptibility to colitis using C3H/HeJBir.IL-10-/- and C57BL/6.IL-10-/- strains. These projects will be supported by an Administrative Core which will provide administrative support and coordination, and an pathogenic analysis, and generate stocks of genetically modified mice for us in the projects. The long-term goal of this Program Project is to increase our understanding of the fundamental mechanisms of chronic intestinal inflammation to develop between therapies for patients with IBD, such as the manipulation of intestinal immune cells and functions to prevent or inhibit disease.